tbuckley/cabot-search huggingface dataset:
Precision functional MRI mapping reveals distinct connectivity patterns for depression associated with traumatic brain injury
Authors: Shan H. Siddiqi, Sridhar Kandala, Carl D. Hacker, Heather Bouchard, Eric C. Leuthardt, Maurizio Corbetta, Rajendra A. Morey, David L. Brody
Journal: Science Translational Medicine (2023)

Depression associated with traumatic brain injury (TBI) is believed to be clinically distinct from primary major depressive disorder (MDD) and may be less responsive to conventional treatments. Brain connectivity differences between the dorsal attention network (DAN), default mode network (DMN), and subgenual cingulate have been implicated in TBI and MDD. To characterize these distinctions, we applied precision functional mapping of brain network connectivity to resting-state functional magnetic resonance imaging data from five published patient cohorts, four discovery cohorts ( n = 93), and one replication cohort ( n = 180). We identified a distinct brain connectivity profile in TBI-associated depression that was independent of TBI, MDD, posttraumatic stress disorder (PTSD), depression severity, and cohort. TBI-associated depression was independently associated with decreased DAN–subgenual cingulate connectivity, increased DAN-DMN connectivity, and the combined effect of both. This effect was stronger when using precision functional mapping relative to group-level network maps. Our results support the possibility of a physiologically distinct “TBI affective syndrome,” which may benefit from individualized neuromodulation approaches to target its distinct neural circuitry.
Broadly neutralizing antibody treatment maintained HIV suppression in children with favorable reservoir characteristics in Botswana
Authors: Roger L. Shapiro, Gbolahan Ajibola, Kenneth Maswabi, Michael Hughes, Bryan S. Nelson, Aischa Niesar, Molly Pretorius Holme, Kathleen M. Powis, Maureen Sakoi, Oganne Batlang, Sikhulile Moyo, Terence Mohammed, Comfort Maphorisa, Kara Bennett, Zixin Hu, Francoise Giguel, Jacqueline D. Reeves, Michael A. Reeves, Ce Gao, Xu Yu, Margaret E. Ackerman, Adrian McDermott, Marlene Cooper, Marina Caskey, Lucio Gama, Patrick Jean-Philippe, Dwight E. Yin, Edmund V. Capparelli, Shahin Lockman, Joseph Makhema, Daniel R. Kuritzkes, Mathias Lichterfeld
Journal: Science Translational Medicine (2023)

Broadly neutralizing antibodies (bNAbs) may provide an alternative to standard antiretroviral treatment (ART) for controlling HIV-1 replication and may have immunotherapeutic effects against HIV-1 reservoirs. We conducted a prospective clinical trial with two HIV-1 bNAbs (VRC01LS and 10-1074) in children ( n = 25) who had previously initiated small-molecule ART treatment before 7 days of age and who continued treatment for at least 96 weeks. Both bNAbs were dosed intravenously every 4 weeks, overlapping with ART for at least 8 weeks and then continued for up to 24 weeks or until detectable viremia of HIV-1 RNA rose above 400 copies per milliliter in the absence of ART. Eleven (44%) children maintained HIV-1 RNA below 400 copies per milliliter through 24 weeks of bNAb-only treatment; 14 (56%) had detectable viremia above 400 copies per milliliter at a median of 4 weeks. Archived HIV-1 provirus susceptible to 10-1074, lower birth HIV-1 DNA reservoir in peripheral blood mononuclear cells, sustained viral suppression throughout early life, and combined negative qualitative HIV-1 DNA polymerase chain reaction and negative HIV-1 serology at entry were associated with maintaining suppression on bNAbs alone. This proof-of-concept study suggests that bNAbs may represent a promising treatment modality for infants and children living with HIV-1. Future studies using newer bNAb combinations with greater breadth and potency are warranted.
Dysregulated IFN-γ signals promote autoimmunity in STAT1 gain-of-function syndrome
Authors: Andrea D. Largent, Katharina Lambert, Kristy Chiang, Natali Shumlak, Denny Liggitt, Mohammed Oukka, Troy R. Torgerson, Jane H. Buckner, Eric J. Allenspach, David J. Rawlings, Shaun W. Jackson
Journal: Science Translational Medicine (2023)

Heterozygous signal transducer and activator of transcription 1 (
Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Steven B. Maron, Walid Chatila, Henry Walch, Joanne F. Chou, Nicholas Ceglia, Ryan Ptashkin, Richard Kinh Gian Do, Viktoriya Paroder, Neeta Pandit-Taskar, Jason S. Lewis, Tiago Biachi De Castria, Shalom Sabwa, Fiona Socolow, Lara Feder, Jasmine Thomas, Isabell Schulze, Kwanghee Kim, Arijh Elzein, Viktoria Bojilova, Matthew Zatzman, Umesh Bhanot, Rebecca J. Nagy, Jeeyun Lee, Marc Simmons, Michal Segal, Geoffrey Yuyat Ku, David H. Ilson, Marinela Capanu, Jaclyn F. Hechtman, Taha Merghoub, Sohrab Shah, Nikolaus Schultz, David B. Solit, Yelena Y. Janjigian
Journal: Clinical Cancer Research (2023)

We report updated clinical outcomes from a phase II study of pembrolizumab, trastuzumab, and chemotherapy (PTC) in metastatic esophagogastric cancer in conjunction with outcomes from an independent Memorial Sloan Kettering (MSK) cohort.
HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress‐driven hepatocellular carcinoma progression
Authors: Lin He, Hao Li, Can Li, Ze‐Kun Liu, Meng Lu, Ren‐Yu Zhang, Dong Wu, Ding Wei, Jie Shao, Man Liu, Hao‐Lin Wei, Cong Zhang, Zhe Wang, Ling‐Min Kong, Zhi‐Nan Chen, Huijie Bian
Journal: Cancer Communications (2023)

Abstract Background The mechanism of hepatitis B virus (HBV)‐induced carcinogenesis remains an area of interest. The accumulation of hepatitis B surface antigen in the endoplasmic reticulum (ER) of hepatocytes stimulates persistent ER stress. Activity of the unfolded protein response (UPR) pathway of ER stress may play an important role in inflammatory cancer transformation. How the protective UPR pathway is hijacked by cells as a tool for malignant transformation in HBV‐related hepatocellular carcinoma (HCC) is still unclear. Here, we aimed to define the key molecule hyaluronan‐mediated motility receptor (HMMR) in this process and explore its role under ER stress in HCC development. Methods An HBV‐transgenic mouse model was used to characterize the pathological changes during the tumor progression. Proteomics and transcriptomics analyses were performed to identify the potential key molecule, screen the E3 ligase, and define the activation pathway. Quantitative real‐time PCR and Western blotting were conducted to detect the expression of genes in tissues and cell lines. Luciferase reporter assay, chromatin immunoprecipitation, coimmunoprecipitation, immunoprecipitation, and immunofluorescence were employed to investigate the molecular mechanisms of HMMR under ER stress. Immunohistochemistry was used to clarify the expression patterns of HMMR and related molecules in human tissues. Results We found sustained activation of ER stress in the HBV‐transgenic mouse model of hepatitis‐fibrosis‐HCC. HMMR was transcribed by c/EBP homologous protein (CHOP) and degraded by tripartite motif containing 29 (TRIM29) after ubiquitination under ER stress, which caused the inconsistent expression of mRNA and protein. Dynamic expression of TRIM29 in the HCC progression regulated the dynamic expression of HMMR. HMMR could alleviate ER stress by increasing autophagic lysosome activity. The negative correlation between HMMR and ER stress, positive correlation between HMMR and autophagy, and negative correlation between ER stress and autophagy were verified in human tissues. Conclusions This study identified the complicated role of HMMR in autophagy and ER stress, that HMMR controls the intensity of ER stress by regulating autophagy in HCC progression, which could be a novel explanation for HBV‐related carcinogenesis.
Whole-genome Duplications and the Long-term Evolution of Gene Regulatory Networks in Angiosperms
Authors: Fabricio Almeida-Silva, Yves Van de Peer
Journal: Molecular Biology and Evolution (2023)

Angiosperms have a complex history of whole-genome duplications (WGDs), with varying numbers and ages of WGD events across clades. These WGDs have greatly affected the composition of plant genomes due to the biased retention of genes belonging to certain functional categories following their duplication. In particular, regulatory genes and genes encoding proteins that act in multiprotein complexes have been retained in excess following WGD. Here, we inferred protein-protein interaction (PPI) networks and gene regulatory networks (GRNs) for seven well-characterized angiosperm species and explored the impact of both WGD and small-scale duplications (SSDs) in network topology by analyzing changes in frequency of network motifs. We found that PPI networks are enriched in WGD-derived genes associated with dosage-sensitive intricate systems, and strong selection pressures constrain the divergence of WGD-derived genes at the sequence and PPI levels. WGD-derived genes in network motifs are mostly associated with dosage-sensitive processes, such as regulation of transcription and cell cycle, translation, photosynthesis, and carbon metabolism, whereas SSD-derived genes in motifs are associated with response to biotic and abiotic stress. Recent polyploids have higher motif frequencies than ancient polyploids, whereas WGD-derived network motifs tend to be disrupted on the longer term. Our findings demonstrate that both WGD and SSD have contributed to the evolution of angiosperm GRNs, but in different ways, with WGD events likely having a more significant impact on the short-term evolution of polyploids.
Targeted anti-interleukin-17 therapy for linear porokeratosis
Authors: Donglin Li, Kristin Technau-Hafsi, Katrin Giehl, Peter H Hoeger, Cristina Has
Journal: British Journal of Dermatology (2023)

We report a case involving a 12-year-old female patient with linear porokeratosis (LP) associated with the PMVK pathogenic variant c.329C&amp;gt;A, p.R110Q (monoallelic in DNA from blood and biallelic in DNA from LP). Therapeutic measures, which included a statin/cholesterol cream, did not ameliorate the patient’s skin lesions. Our findings demonstrate a strong interleukin (IL)-17A-positive inflammatory infiltrate, upregulation of IL-17-responsive genes and a significant clinical response to anti-IL-17A therapy in LP.
Sequencing of Endocrine and Targeted Therapies in Hormone-Sensitive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer
Authors: Emily B. Jackson, Stephen K.L. Chia
Journal: Journal of Clinical Oncology (2023)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice. Optimizing the selection and sequencing of endocrine and targeted therapies for hormone-sensitive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer is a rapidly evolving field owing in large part to an increasing pace of drug development coupled with a greater understanding of the genomic drivers of breast cancer. The recently published results from the MAINTAIN clinical trial begin to answer an important question in this patient population—can the well-established benefit with first-line cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors be stretched further by continuing this drug class beyond progression and selecting an alternate endocrine therapy partner? We present a case of a patient with hormone-sensitive HER2 low metastatic breast cancer who underwent circulating tumor DNA next-generation sequencing to better inform her treatment options after progression on first-line therapy with a CDK 4/6 inhibitor and aromatase inhibitor. Our clinical approach in this patient population prioritizes the identification of actionable mutations with high-quality evidence for efficacy on the basis of clinical trials post-CDK 4/6 inhibitors, while balancing comorbidities and patient priorities for care. Several recent clinical trials discussed herein present clinically meaningful results linking emerging targeted therapies to actionable alterations in PIK3CA, ESR1, AKT1, and PTEN. Continued drug development in this space delays time to treatment with chemotherapy, and hopefully contributes to maintaining a high quality of life for these patients on primarily oral-based therapy.
Activation of autophagy by in situ Zn2+ chelation reaction for enhanced tumor chemoimmunotherapy
Authors: Yang Yang, Yefei Zhu, Kairuo Wang, Yunqiu Miao, Yuanyuan Zhang, Jie Gao, Huanlong Qin, Yang Zhang
Journal: Bioactive Materials (2023)

Chemotherapy can induce a robust T cell antitumor immune response by triggering immunogenic cell death (ICD), a process in which tumor cells convert from nonimmunogenic to immunogenic forms. However, the antitumor immune response of ICD remains limited due to the low immunogenicity of tumor cells and the immunosuppressive tumor microenvironment. Although autophagy is involved in activating tumor immunity, the synergistic role of autophagy in ICD remains elusive and challenging. Herein, we report an autophagy amplification strategy using an ion-chelation reaction to augment chemoimmunotherapy in cancer treatments based on zinc ion (Zn2+)-doped, disulfiram (DSF)-loaded mesoporous silica nanoparticles (DSF@Zn-DMSNs). Upon pH-sensitive biodegradation of DSF@Zn-DMSNs, Zn2+ and DSF are coreleased in the mildly acidic tumor microenvironment, leading to the formation of toxic Zn2+ chelate through an in situ chelation reaction. Consequently, this chelate not only significantly stimulates cellular apoptosis and generates damage-associated molecular patterns (DAMPs) but also activates autophagy, which mediates the amplified release of DAMPs to enhance ICD. In vivo results demonstrated that DSF@Zn-DMSNs exhibit strong therapeutic efficacy via in situ ion chelation and possess the ability to activate autophagy, thus enhancing immunotherapy by promoting the infiltration of T cells. This study provides a smart in situ chelation strategy with tumor microenvironment-responsive autophagy amplification to achieve high tumor chemoimmunotherapy efficacy and biosafety.
Flashback Foreword: Multigene Predictor for Chemotherapy Response in Breast Cancer
Authors: Antonio C. Wolff
Journal: Journal of Clinical Oncology (2023)

Article Tools FLASHBACK FOREWORD Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor–Positive Breast Cancer. July 05, 2023 ARTICLE CITATION DOI: 10.1200/JCO.23.00243 Journal of Clinical Oncology - published online before print July 5, 2023 PMID: 37406455 Flashback Foreword: Multigene Predictor for Chemotherapy Response in Breast Cancer Antonio C. Wolff , MD, FACP, FASCO1,2xAntonio C. WolffSearch for articles by this author Show More 1Former Associate Editor, Journal of Clinical Oncology, Alexandria, VA2The Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD https://doi.org/10.1200/JCO.23.00243 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologyTHE TAKEAWAYIn the companion to this article, Paik et al1 demonstrated that a 21-gene recurrence score assay identified the patients expected to benefit from the addition of adjuvant chemotherapy to 5 years of tamoxifen in patients with estrogen receptor–positive, node-negative breast cancer. These findings ushered a new era that increasingly focuses on optimizing therapies for all patients (more for some, less for others) and on improving the accuracy and reproducibility of biomarkers used for clinical decision making.AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTFlashback Foreword: Multigene Predictor for Chemotherapy Response in Breast CancerThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Antonio C. WolffResearch Funding: Genentech (Inst), Merck Sharp & Dohme (Inst), Array BioPharma (Inst)Patents, Royalties, Other Intellectual Property: Antonio Wolff has been named as an inventor on one or more issued patents or pending patent applications related to methylation in breast cancer, has assigned his rights to JHU, and participates in a royalty sharing agreement with JHUNo other potential conflicts of interest were reported. Companion Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor–Positive Breast Cancer
A metal ions-mediated natural small molecules carrier-free injectable hydrogel achieving laser-mediated photo-Fenton-like anticancer therapy by synergy apoptosis/cuproptosis/anti-inflammation
Authors: Wenmin Pi, Linying Wu, Jihui Lu, Xiaoyu Lin, Xuemei Huang, Zhijia Wang, Zhihua Yuan, Hailing Qiu, Jianglan Zhang, Haimin Lei, Penglong Wang
Journal: Bioactive Materials (2023)

Tumor microenvironment (TME) plays an important role in the tumorigenesis, proliferation, invasion and metastasis. Thereby developing synergistic anticancer strategies with multiple mechanisms are urgent. Copper is widely used in the treatment of tumor chemodynamic therapy (CDT) due to its excellent laser-mediated photo-Fenton-like reaction. Additionally, copper can induce cell death through cuproptosis, which is a new modality different from the known death mechanisms and has great promise in tumor treatment. Herein, we report a natural small molecules carrier-free injectable hydrogel (NCTD Gel) consisted of Cu2+-mediated self-assembled glycyrrhizic acid (GA) and norcantharidin (NCTD), which are mainly governed by coordination and hydrogen bonds. Under 808 nm laser irradiation, NCTD Gel can produce reactive oxygen species (ROS), consume glutathione (GSH) and overcome hypoxia in TME, leading to synergistically regulate TME via apoptosis, cuproptosis and anti-inflammation. In addition, NCTD Gel's CDT display high selectivity and good biocompatibility as it relies on the weak acidity and H2O2 overexpression of TME. Notably, NCTD Gel's components are originated from clinical agents and its preparation process is easy, green and economical, without any excipients. This study provides a new carrier-free hydrogel synergistic antitumor strategy, which has a good prospect in industrial production and clinical transformation.
Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor–Positive Breast Cancer
Authors: Soonmyung Paik, Gong Tang, Steven Shak, Chungyeul Kim, Joffre Baker, Wanseop Kim, Maureen Cronin, Frederick L. Baehner, Drew Watson, John Bryant, Joseph P. Costantino, Charles E. Geyer, D. Lawrence Wickerham, Norman Wolmark
Journal: Journal of Clinical Oncology (2023)

PURPOSE The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor–positive, lymph node–negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. METHODS The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy–treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. RESULTS A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant ( P = .038). Patients with high-RS (≥ 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS (&lt; 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, −1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit. CONCLUSION The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor–positive breast cancer, but also predicts the magnitude of chemotherapy benefit.
The role of E3 ubiquitin ligases in bone homeostasis and related diseases
Authors: Yuechao Dong, Yangshan Chen, Guixing Ma, Huiling Cao
Journal: Acta Pharmaceutica Sinica B (2023)

The ubiquitin–proteasome system (UPS) dedicates to degrade intracellular proteins to modulate demic homeostasis and functions of organisms. These enzymatic cascades mark and modifies target proteins diversly through covalently binding ubiquitin molecules. In the UPS, E3 ubiquitin ligases are the crucial constituents by the advantage of recognizing and presenting proteins to proteasomes for proteolysis. As the major regulators of protein homeostasis, E3 ligases are indispensable to proper cell manners in diverse systems, and they are well described in physiological bone growth and bone metabolism. Pathologically, classic bone-related diseases such as metabolic bone diseases, arthritis, bone neoplasms and bone metastasis of the tumor, etc., were also depicted in a UPS-dependent manner. Therefore, skeletal system is versatilely regulated by UPS and it is worthy to summarize the underlying mechanism. Furthermore, based on the current status of treatment, normal or pathological osteogenesis and tumorigenesis elaborated in this review highlight the clinical significance of UPS research. As a strategy possibly remedies the limitations of UPS treatment, emerging PROTAC was described comprehensively to illustrate its potential in clinical application. Altogether, the purpose of this review aims to provide more evidence for exploiting novel therapeutic strategies based on UPS for bone associated diseases.
Correction: Integrative analysis identifies an older female-linked AML patient group with better risk in ECOG-ACRIN Cancer Research Group’s clinical trial E3999
Authors: Franck Rapaport, Kenneth Seier, Yaseswini Neelamraju, Duane Hassane, Timour Baslan, Daniel T. Gildea, Samuel Haddox, Tak Lee, H. Moses Murdock, Caroline Sheridan, Alexis Thurmond, Ling Wang, Martin Carroll, Larry D. Cripe, Hugo Fernandez, Christopher E. Mason, Elisabeth Paietta, Gail J. Roboz, Zhuoxin Sun, Martin S. Tallman, Yanming Zhang, Mithat Gönen, Ross Levine, Ari M. Melnick, Maria Kleppe, Francine E. Garrett-Bakelman
Journal: Blood Cancer Journal (2023)

Following the publication of this article, the authors noted an error in sample reporting.Eleven specimens included in the original data were follow up specimens taken from patients after initial therapy, and not diagnostic specimens sampled prior to initial therapy.To correct for this error, and to accurately report on findings in pre-therapy samples which have prognostic value, data from the 11 samples have now been excluded and the data re-analyzed.